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United States Patent |
5,246,964
|
Ueno
|
September 21, 1993
|
Treatment of inflammatory diseases with polyoxyethylenesorbitan
mono-higher-fatty acid esters
Abstract
A method of treatment of inflammatory diseases which comprises
administering, to a subject in need of such treatment, an
anti-inflammatory effective amount of a polyoxyethylenesorbitan
mono-higher-fatty acid ester.
Inventors:
|
Ueno; Ryuji (Hyogo, JP)
|
Assignee:
|
K.K. Ueno Seiyaku Oyo Kenkyujo (Osaka, JP)
|
Appl. No.:
|
726673 |
Filed:
|
July 8, 1991 |
Foreign Application Priority Data
Current U.S. Class: |
514/473; 514/886; 514/887; 514/914 |
Intern'l Class: |
A61K 031/34 |
Field of Search: |
514/473,886,887,914
|
References Cited
Other References
Proceedings of the Society for Experimental Biology and Medicine, vol. 184,
No. 4, 1987, pp. 477-482.
|
Primary Examiner: Waddell; Frederick E.
Assistant Examiner: Jordan; Kimberly R.
Attorney, Agent or Firm: Sughrue, Mion, Zinn, Macpeak & Seas
Claims
What is claimed is:
1. A method of treatment of inflammation which comprises administering, to
a subject in need of such treatment, an amount effective for treating
inflammation of a polyoxyethylenesorbitan mono-higher-fatty acid ester.
2. The method according to claim 1, in which the higher-fatty acid is a
fatty acid having 10 to 24 carbon atoms.
3. The method according to claim 1, in which the polyoxyethylenesorbitan is
formed by reacting sorbitan with 15 to 25 moler excess of ethylene oxide.
4. The method according to claim 1, in which the higher-fatty acid is
unsaturated.
5. The method according to claim 1, in which the polyoxyethylenesorbitan
mono-higher-fatty acid ester is polyoxyethylene(20)sorbitan mono oleate.
6. The method according to claim 1, in which the polyoxyethylenesorbitan
mono-higher-fatty acid ester is topically administered.
7. The method according to claim 1, wherein the inflammation associated
with conjunctivitis, iritis, uveitis, central retinitis, external otitis,
acute suppurative otitis media, mastoiditis, labyrinthitis, chronic
rhinitis, acute rhinitis, sinusitis, pharyngitis, tonsillitis, chronic
bronchitis, acute bronchiolitis, lobar pneumonia, bronchopneumonia,
primary atypical pneumonia, dry pleurisy, wet pleurisy, mediastinitis,
acute rheumatic endocarditis, bacterial endocarditis, thrombophlebitis,
polyarteritis, acute nephritis, chronic nephritis, cystitis,
paranephlitis, stomatitis, esophagitis, acute gastritis, chronic
gastritis, ulcertive colitis, acute appendicitis, chronic hepatitis, acute
hepatitis, cholangiolitic hepatitis, cholecystitis, chronic pancreatitis,
acute pancreatitis, chronic peritonitis, acute peritonitis, thyroiditis,
contact dermatitis, acute hemorrhagic encephalitis, purulent meningitis,
optic neuromyelitis, alcoholic polyneuritis, diabetic polyneuritis,
polymyositis, myositis ossificans, degenerative arthritis, rheumatoid
arthritis, periarthritis scapulohumeralis or osteitis deformans is
treated.
8. The method according to claim 1, wherein the inflammation treated
affects the eye.
9. The method according to claim 7, wherein conjunctivitis, iritis, uveitis
or central retinitis is treated.
10. The method of claim 7, wherein conjunctivitis is treated.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a treatment of inflammatory diseases with
polyoxyethylenesorbitan mono-higher-fatty acid esters which have been used
as surfactants.
2. Background Information
It is well known that polyoxyethylenesorbitan mono-higher-fatty acid esters
can be used as surfactants for emulsifying or dispersing purpose. It is
also known that polyoxyethylenesorbitan monooleate (also known as
Polysorbate 80) is a substance inducing the release of histamine (Agents
and Actions, 16, 470-477).
As a result of extensive studies about the biological properties of
polyoxyethylenesorbitan mono-higher-fatty acid esters, the present
inventor have discovered that these compounds are useful as an agent for
treating inflammatory diseases.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a method for treatment of
inflammatory diseases which comprises administering, to a subject in need
of such treatment, an anti-inflammatorily effective amount of a
polyoxyethylenesorbitan mono-higher-fatty acid ester.
In a second aspect, the present invention provides a use of
polyoxyethylenesorbitan mono-higher-fatty acid ester for the manufacture
of a medicament for treatment of inflammatory diseases.
In a third aspect, the present invention provides a pharmaceutical
composition for treatment of inflammatory diseases comprising a
polyoxyethylenesorbitan mono-higher-fatty acid ester in association with a
pharmaceutically acceptable carrier, diluent or excipient.
DETAILED DESCRIPTION OF THE INVENTION
The term "inflammatory disease" means lesions caused by a defensive
reaction or an inflammatory reaction of a living body against harmful
influence of circumstances (such as physical, chemical and biological
circumstances) having signs of redness, heat, pain, swelling and loss of
function.
The term "anti-inflammatory" means a tendency or an ability to act against
or protect from or inhibit the inflammatory reaction. The
polyoxyethylenesorbitan mono-higher-fatty acid esters used in the instant
invention have such tendency or ability.
The inflammatory diseases includes conjunctivitis, iritis, uveitis, central
retinitis, external otitis, acute suppurative otitis media, mastoiditis,
labyrinthitis, chronic rhinitis, acute rhinitis, sinusitis, pharyngitis,
tonsillitio, chronic bronchitis, acute bronchilotis, lobar pneumonia,
bronchopneumonia, primary atypical pneumonia, dry pleurisy, wet pleurisy,
mediastinitis, acute rheumatic endocarditis, bacterial endocarditis,
thrombophlebitis, polyarteritis, acute nephritis, chronic nephritis,
cystitis, paranephlitis, stomatitis, esophagitis, acute gastritis, chronic
gastritis, ulcertive colitis, acute appendicitis, chronic hepatitis, acute
hepatitis, cholangiolitic hepatitis, cholecystitis, chronic pancreatitis,
acute pancreatitis, chronic peritonitis, acute peritonitis, thyroiditis,
contact dermatitis, acute hemorrhagic encephalitis, purulent meningitis,
optic neuromyelitis, alcohlic polyneuritis, diabetic polyneuritis,
polymyositis, myositis ossificans, degenerative arthritis, rheumatoid
arthritis, periarthritis scapulohumeralis, osteitis deformans, etc.
The polyoxyethylenesorbitan mono-higher-fatty acid esters used in the
present invention are mono ester of polyoxyethylenesorbitan with
higher-fatty acids, said polyoxyethylenesorbitan being formed by reacting
sorbitan with ordinarily 15 to 25 molar excess and preferably about 20
molar excess of ethylene oxide, and may contain a little amount of di- or
tri-esters. The above molar number of ethylene oxide is represented in
round brackets.
The higher-fatty acids include fatty acids having 10 to 24 and preferably
12 to 20 carbon atoms. Such acids include saturated fatty acids and
unsaturated fatty acids. As the saturated fatty acids, lauric acid,
myristic acid, palmitic acid, stearic acid arachidic acid, etc. are
preferred. Polyoxyethylene(20)sorbitan monolaurate is known as Polysorbate
20 and commercialized under the tradename Tween 20.
Polyoxyethylene(20)sorbitan monopalmitate is known as Polysorbate 40 and
commercialized under the tradename Tween 40. Polyoxyethylene(20)sorbitan
monostearate is known as Polysorbate 60 and commercialized under the
tradename Tween 60. As the unsaturated fatty acids, myristoleic acid,
palmitoleic acid, oleic acid, gadoleic acid, linoleic acid etc. are
preferred. Polyethylene(20)sorbitan monooleate is known as Polysorbate 80
and commercialized under the tradenames Sorlate, Tween 80, Monitan and
Olothorb.
Since the polyoxyethylenesorbitan mono-higher-fatty acid esters have action
inhibiting inflammatory reaction, they are useful in treatment of
inflammatory disease. The above compounds may be used as a medicine for
animals and humans. Although the principal route is topical, the
administration of the above compounds is not limited thereto and various
other routes may be possible. While the dosage will vary depending on the
animal or human patient, age, body weight, symptom to be treated, desired
therapeutic effect, route of administration, term of treatment and the
like, satisfactory effects will be obtained with the dosage of 0.01-100
.mu.g/eye administered locally (i.e. ocutarly) or 0.001-500 mg/kg
administered in 2 to 4 divided doses a day or as a sustained form.
The above compounds is usually administered in the form of a pharmaceutical
composition containing at least one of said compounds and optionally other
ingredients conveniently used, such as carrier, diluent or excipient. The
composition includes liquids such as a solution, an emulsion and a
suspension, or semi-solids such as gel and ophthalmic ointment.
Diluents for the aqueous solution or suspension includes, for example,
distilled water an physiological saline. Diluents for the nonoaqueous
solution and suspension include, for example, vegetable oils e.g. olive
oil, liquid paraffin, mineral oil, and propylene glycol and
p-octyldodecanol. The composition may also contain isotonization agents
such as sodium chloride, boric acid, sodium citrate, etc. to make isotonic
with the lacrimal fluid and buffering agents such as borate buffer,
phosphate buffer, etc. to maintain pH about 5.0 to 8.0. Further,
stabilizers such as sodium sulfite, propylene glycol, etc., chelating
agents such as sodium edetate, etc., thickeners such as glycerol,
carboxymethylcellulose, carboxyvinyl polymer, etc. and preservatives such
as methyl paraben, propyl paraben, benzalkonium chloride, cetylpyridinium
chloride, chlorobutanol, etc. may also added. These can be sterilized e.g.
by passing through a bacterial filter or by heating.
The ophthalmic ointment may contain vaseline, Plastibase, Macrogol etc. as
a base and surfactant for increasing hydrophilicity. It may also contain
geling agents such as carboxymethylcellulose, methylcellulose, caboxyvinyl
polymer, etc.
In addition, the composition may contain antibiotics such as
chloramphenicol, penicilin, etc. in order to prevent or treat bacterial
infection.
A more complete understanding of the present invention can be obtained by
reference to the following Formulation Examples and Test Examples which
are provided herein for purpose of illustrating only and are not intended
to limit the scope of the invention.
FORMULATION EXAMPLE 1
______________________________________
polyoxyethylene (20) sorbitan 1.0 g
monooleate (polysorbate 80)
sodium chloride 0.8 g
distilled water q.s. to 100 ml
______________________________________
TEST EXAMPLE 1
The composition of Formulation Example 1 was topically administered to both
eyes of mice at a dose of 5 .mu.l per eye. Three minutes after the
administration, 0.5% Evans Blue in physiological saline (0.5 ml) was
injected in the caudal vein. Immediately after, 0.01% histamine in
physiological saline (50 .mu.l) was injected subconjunctivally at an upper
eyelid. After 30 minutes, the animals were sacrificed by vertebral cervial
dislocation and the scalp was peeled away towards the eyelid. Part of skin
and conjunctive showing inflammation was cut off and weighed.
Then, said conjunctive was minced and extracted overnight with 4 ml
formaldehyde at 40.degree. C. with shaking. The dye in the conjunctive was
assayed by measuring absorption of the extract at 625 nm.
The results are shown in Table 1.
TABLE 1
______________________________________
Weight of
Number of
conjunctive Dye
Animals (Mean .+-. S.D.)
(.mu.g/part)
______________________________________
Control 26 38.2 .+-. 1.8
5.59 .+-. 0.36
Formulation
24 36.8 .+-. 1.4
4.76 .+-. 0.22*
Example 1
______________________________________
*T-Test, P < 0.1
The above results show that the tested compound has an activity inhibiting
experimental inflammation.
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